Oncogenic Splicing Factor SRSF1 Is a Critical Transcriptional Target of MYC

SummaryThe SR protein splicing factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer. Here, we show that SRSF1 is a direct target of the transcription factor oncoprotein MYC. These two oncogenes are significantly coexpressed in lung carcinomas, and MYC knockdown downregulates SRSF1 expression in lung-cancer cell lines. MYC directly activates transcription of SRSF1 through two noncanonical E-boxes in its promoter. The resulting increase in SRSF1 protein is sufficient to modulate alternative splicing of a subset of transcripts. In particular, MYC induction leads to SRSF1-mediated alternative splicing of the signaling kinase MKNK2 and the transcription factor TEAD1. SRSF1 knockdown reduces MYC's oncogenic activity, decreasing proliferation and anchorage-independent growth. These results suggest a mechanism for SRSF1 upregulation in tumors with elevated MYC and identify SRSF1 as a critical MYC target that contributes to its oncogenic potential by enabling MYC to regulate the expression of specific protein isoforms through alternative splicing.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► MYC and SRSF1 are significantly coexpressed in lung and breast cancers ► SRSF1 is a direct transcriptional target of MYC ► A subset of SRSF1 targets show alternative splicing changes in response to MYC induction ► SRSF1 knockdown reduces MYC-mediated transformation